Open Access
Evidence for a Common Mechanism of SIRT1 Regulation by Allosteric Activators
Basil P. Hubbard,Ana P. Gomes,Han Dai,Jun Li,April Case,Thomas Considine,Thomas V. Riera,Jessica E. Lee,E. Sook Yen,Dudley W. Lamming,Eli Schuman,Linda Stevens,Alvin J. Y. Ling,Sean M. Armour,Shaday Michan,Huizhen Zhao,Yong Jiang,Sharon Sweitzer,Charles A. Blum,Jeremy S. Disch,Pui Yee Ng,Konrad T. Howitz,Anabela P. Rolo,Yoshitomo Hamuro,Joel Moss,Robert B. Perni,James L. Ellis,George P. Vlasuk,David A. Sinclair,Bradley L. Pentelute +29 more
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TLDR
Yuan et al. as mentioned in this paper found that specific hydrophobic motifs found in SIRT1 substrates such as PGC-1α and FOXO3a facilitate SIRT 1 activation by STACs.Abstract:
It's a SIRT Intense attention has focused on the SIRT1 deacetylase as a possible target for anti-aging drugs. But unexpected complications in assays of SIRT1 activity have made it unclear whether compounds thought to be sirtuin-activating compounds (STACs) are really direct regulators of the enzyme. Further exploration of these effects by Hubbard et al. (p. 1216; see the Perspective by Yuan and Marmorstein) revealed that interaction of SIRT1 with certain substrates allows activation of SIRT1 by STACs and identified critical amino acids in SIRT1 required for these effects. Mouse myoblasts reconstituted with SIRT1 mutated at this amino acid lost their responsiveness to STACs. An interaction of the deacetylase SIRT1 with its substrate offers a possible explanation for some effects on aging. [Also see Perspective by Yuan and Marmorstein] A molecule that treats multiple age-related diseases would have a major impact on global health and economics. The SIRT1 deacetylase has drawn attention in this regard as a target for drug design. Yet controversy exists around the mechanism of sirtuin-activating compounds (STACs). We found that specific hydrophobic motifs found in SIRT1 substrates such as PGC-1α and FOXO3a facilitate SIRT1 activation by STACs. A single amino acid in SIRT1, Glu230, located in a structured N-terminal domain, was critical for activation by all previously reported STAC scaffolds and a new class of chemically distinct activators. In primary cells reconstituted with activation-defective SIRT1, the metabolic effects of STACs were blocked. Thus, SIRT1 can be directly activated through an allosteric mechanism common to chemically diverse STACs.read more
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Phenolics and polyphenolics in foods, beverages and spices: Antioxidant activity and health effects – A review
TL;DR: A review of phenolic and polyphenolic compounds can be found in this article, which summarizes both the synthetic and natural phenolic antioxidants, emphasizing their mode of action, health effects, degradation products and toxicology.
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Declining NAD + Induces a Pseudohypoxic State Disrupting Nuclear-Mitochondrial Communication during Aging
Ana P. Gomes,Ana P. Gomes,Nathan L. Price,Alvin J. Y. Ling,Javid Moslehi,Magdalene K. Montgomery,Luis A. Rajman,James P. White,João S. Teodoro,Christiane D. Wrann,Basil P. Hubbard,Evi M. Mercken,Carlos M. Palmeira,Rafael de Cabo,Anabela P. Rolo,Nigel Turner,Eric L. Bell,David A. Sinclair,David A. Sinclair +18 more
TL;DR: It is shown that, during aging, there is a specific loss of mitochondrial, but not nuclear, encoded OXPHOS subunits, and an alternate PGC-1α/β-independent pathway of nuclear-mitochondrial communication contributes to the decline in mitochondrial function with age.
SIRT1 and other sirtuins in metabolism
Hung-Chun Chang,Leonard Guarente +1 more
TL;DR: This review will cover these topics and suggest that strategies to maintain sirtuin activity may be on the horizon to forestall diseases of aging.
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50 years of protein acetylation: from gene regulation to epigenetics, metabolism and beyond
Eric Verdin,Melanie Ott +1 more
TL;DR: Progress accomplished during the past 50 years of histone acetyltransferases, histone deacetylases and acetyl-Lys-binding proteins, and the future of protein acetylation are reviewed.
References
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Negative Regulation of STAT3 Protein-mediated Cellular Respiration by SIRT1 Protein
Michel Bernier,Rajib K. Paul,Alejandro Martin-Montalvo,Morten Scheibye-Knudsen,Shaoming Song,Hua-Jun He,Sean M. Armour,Basil P. Hubbard,Vilhelm A. Bohr,Lili Wang,Yaping Zong,David A. Sinclair,Rafael de Cabo +12 more
TL;DR: SIRT1 appears to be a functional regulator of NF-κB-dependent STAT3 expression that induces mitochondrial biogenesis and has implications for understanding the interplay between STAT3 and SIRT1 in pro-inflammatory conditions.
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A continuous microplate assay for sirtuins and nicotinamide-producing enzymes.
TL;DR: This assay is applicable to any nicotinamide-forming enzyme and will be an important tool to address many outstanding questions surrounding their regulation and is readily adaptable to high-throughput screening.
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Peptide Switch Is Essential for Sirt1 Deacetylase Activity
TL;DR: It is found within the C-terminal domain a 25 aa sequence that is essential for Sirt1 activity (ESA) that interacts with and functions as an "on switch" for the deacetylase core.
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SIRT1 contains N- and C-terminal regions that potentiate deacetylase activity
TL;DR: It is shown that the N- and C-terminal regions stimulate SIRT1 deacetylase activity intramolecularly and that the C-Terminal region stably associates with the catalytic core domain to form a Sirt1 holoenzyme.
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SIRT1 associates with eIF2-alpha and regulates the cellular stress response
TL;DR: SIRT1 co-immunoprecipitates with mediators of eIF2α dephosphorylation, GADD34 and CreP, suggesting a role for SIRT1 in the negative feedback regulation of eif2α phosphorylation.